Following our previous therapeutic success with cyclophosphamide (CP) in the treatment of Wegener's granulomatosis (WG), we have gone on to evaluate the safety and efficacy of methotrexate (MTX) as an alternative therapy in this disease. Forty-two patients who did not have immediately life-threatening disease were studied. Glomerulonephritis was present in 21/42 (50%) of patients. The median follow-up was 33.7 months. Weekly administration of MTX and prednisone resulted in remission of disease in 34/42 patients (80%). The median time to remission was 4.2 months. Fifteen of the 34 patients achieving remission experienced a relapse of disease. The estimated median time to relapse for all patients achieving remission was 32 months. Ten patients who relapsed were treated with a second course of MTX plus prednisone. A second remission was induced in 8 out of 10 patients. Thus, MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. In preliminary studies we have used skin blisters induced by suction as a method to study the in vivo inflammatory response of patients with WG. We have shown that patients with active WG produce 50- to 100-fold higher levels of TNF-alpha in blister fluid when compared with normal controls. Such high TNF-alpha levels are not seen in blister fluid from patients with a variety of other inflammatory and infectious diseases. Levels of IL-1beta and IL-6 were also significantly elevated in blister fluid from patients with active WG. These findings have important therapeutic implications since specific inhibitors of TNF-alpha and other pro- inflammatory cytokines are currently available and may be effective in the treatment of WG and related vasculitic syndromes.